Role In Chronic Inflammatory Responses Research Articles

Rheumatoid arthritis

Rheumatoid arthritis (RA) is achronic and progressive systemic disease of the connective tissue, which is particularly manifested with destructive alterations to the joints. Inflammatory reactions in the synovium lead to the influx of peripheral inflammatory cells as well as the activation of local cells. Released growth factors, chemokines and especially cytokines play akey role in chronic inflammatory responses. In addition to the central lymphocytes, the T and Bcells and their subpopulations, locally resident cells, such as neutrophils, macrophages and fibroblasts as well as cells of bone metabolism are activated by the inflammatory milieu and contribute to and drive inflammation and tissue damage. The destruction of cartilage and bone substance by local tissue cells, synovial fibroblasts and osteoclasts is characteristic for this disease. Untreated, the local inflammatory and destructive processes as well as systemic inflammatory factors lead to progressive and irreversible joint destruction. Cellular and immunological processes in RA are closely interwoven; therefore, besides the general inhibition of immunological processes, specific inhibition of central key molecules can reduce or completely stop the inflammatory destructive processes; however, ahigh heterogeneity can be observed among RA patients and disease progression. Therefore, an expansion of the therapeutic options is desirable as not all patients are able to equally benefit from the therapeutic treatment. It is important to characterize new molecular mechanisms, which could lead to the development of new therapeutic options. Some of the more recent insights are summarized in this overview.

TLR2 activation induced by H. pylori LPS promotes the differential expression of claudin-4, -6, -7 and -9 via either STAT3 and ERK1/2 in AGS cells

Gastric carcinogenesis has been associated to H. pylori virulence factors that induce a chronic inflammation process. Lipopolysaccharides play a role in chronic inflammatory responses via TLR2- and TLR4-dependent signaling pathways. Similarly, cellular invasiveness, metastatic potential and prognosis are usually associated to claudin-4, -6, -7 and -9 expression in gastric carcinogenesis. Therefore, the aim of this study was to determine if H. pylori LPS exerts an influence on carcinogenesis-related claudin expression and if it was directly regulated through the TLR2 pathway. Human antrum gastric adenocarcinoma AGS cells exposed or not to H. pylori LPS were used. Polyclonal anti-claudin-4, -6, -7 and -9, anti-TLR2, anti-pERK1/2 as well as rabbit monoclonal anti-pNFκB p65 and mouse monoclonal anti-CdX2 were used. ERK1/2 inhibitor UO126 and STAT3 inhibitor Stattic were also used. Western blot, immunofluorescence and confocal experiments were performed in whole cells as well as total protein, nuclear and cell membrane fractions. The results showed that H. pylori LPS increased the expression of TLR2 in a time dependent bi-phasic manner (<12 and >12h exposure). Immunofluorescence using AGS monolayers corroborated the double phase TLR2 expression mainly on the cell membrane but a detectable signal was also determined in the cytoplasm of the cells. Activation of NFkB was downstream and depended on TLR2 expression as a statistically significant increase in pNFkB, that followed a pattern highly similar to the TLR2 expression was observed on the cell membrane fraction. The increase in TLR2 expression was accompanied by dramatically increased claudin-4 expression in cultures exposed from 30m to 8h to LPS. Increased expression of claudin-6, -7 and -9 also increases in >12h LPS exposure times. The increase in claudins expression was also dependent on NFkB activation. The results also showed an increase in pSTAT3 that followed a bi-phasic pattern that began 30min after stimulation and was compatible with the increase in TLR2 expression. The expression of the claudin-4 related CDX2 transcription factor did not followed the biphasic pattern. The results also showed that claudin-4 expression was STAT3 dependent whereas claudin-6, 7 and 9 expressions was ERK1/2 dependent. Our results suggest that H. pylori LPS induces TLR2 expression in the AGS cells, and that the longer the exposure to LPS, the greater the expression of TLR2 in the cell membrane. Consequently the expression of claudin-4, -6, -7 and -9 also increases.

A novel role for the Krüppel-like factor 14 on macrophage inflammatory response and atherosclerosis development.

Genome-wide association studies have shown that Krüppel-like factor 14 (KLF14) is associated with both Type 2 diabetes mellitus and lipid metabolism. However, its role in chronic inflammatory responses and the pathogenesis of atherosclerosis remains unknown. The present study was designed to investigate both in vivo and in vitro the impact of KLF14 on chronic inflammatory responses and atherosclerosis. ApoE KO mice, a well-established animal model of atherosclerosis, had higher expressions of KLF14 in aorta tissues than that in C57BL/6 J mice when fed the high-fat diet (HFD) or standard chow diet. Adenovirus-mediated KLF14 knockdown markedly reduced the circulating levels of proinflammatory cytokines and the formation of atherosclerotic lesions in HFD-fed ApoE KO mice. In the in vitro study, KLF14 overexpression in the RAW264.7 macrophages significantly increased the expressions of inflammatory cytokines, total cholesterol (TC), cholesteryl ester (CE), and the ratio of CE to TC in the cells treated with acetylated low-density lipoproteins (AcLDL). Conversely, KLF14 knockdown remarkably attenuated AcLDL-induced increase in TC, CE, and the ratio of CE to TC as well as the expressions of inflammatory cytokines. Furthermore, up-regulation or down-regulation of KLF14 markedly elevated or inhibited the phosphorylation levels of p38 MAPK and ERK1/2 in AcLDL-stimulated RAW264.7 macrophages, respectively. Importantly, treatment with p38 MAPK or ERK1/2 inhibitor nullified the effects of KLF14 on inflammatory cytokine expressions in the cells. These data demonstrate an important role for KLF14 expression in atherosclerotic lesion formation.

Apoptotic cell-treated dendritic cells induce immune tolerance by specifically inhibiting development of CD4⁺ effector memory T cells.

CD4(+) memory T cells play an important role in induction of autoimmunity and chronic inflammatory responses; however, regulatory mechanisms of CD4(+) memory T cell-mediated inflammatory responses are poorly understood. Here we show that apoptotic cell-treated dendritic cells inhibit development and differentiation of CD4(+) effector memory T cells in vitro and in vivo. Simultaneously, intravenous transfer of apoptotic T cell-induced tolerogenic dendritic cells can block development of experimental autoimmune encephalomyelitis (EAE), an inflammatory disease of the central nervous system in C57 BL/6J mouse. Our results imply that it is effector memory CD4(+) T cells, not central memory CD4(+) T cells, which play a major role in chronic inflammatory responses in mice with EAE. Intravenous transfer of tolerogenic dendritic cells induced by apoptotic T cells leads to immune tolerance by specifically blocking development of CD4(+) effector memory T cells compared with results of EAE control mice. These results reveal a new mechanism of apoptotic cell-treated dendritic cell-mediated immune tolerance in vivo.

Apoptotic cell-treated dendritic cells induce immune tolerance through specifically facilitating development of CD4+ effector memory T cells (IRC10P.408)

Abstract CD4+ memory T cells play an important role in induction of autoimmunity and chronic inflammatory responses. However, regulatory mechanisms of CD4+ memory T cell-mediated inflammatory responses are poorly understood. Here we showed that apoptotic cell-treated dendritic cells inhibit development and differentiation of CD4+ effector and central memory T cells in vitro and in vivo. Simultaneously, i.v. transfer of apoptotic T cell-induced tolerogenic dendritic cells can block development of experimental autoimmune encephalomyelitis (EAE), an inflammatory disease in central nervous system of C57BL/6J mouse. However, our results imply that it is effector memory CD4+ T cells, not central memory CD4+ T cells which play a major role in chronic inflammatory responses in mice with EAE. I.v. transfer of tolerogenic dendritic cells induced by apoptotic T cells leads to immune tolerance through specifically blocking development of CD4+ effector memory T cells compared with results of EAE control mice. Our results reveal a new mechanism of apoptotic cell-treated dendritic cell-mediated immune tolerance in vivo.

ChemInform Abstract: Synthesis and Immunomodulatory Activities of Helicobacter Pylori Lipophilic Terminus of Lipopolysaccharide Including Lipid A

AbstractReview: 40 refs.

Synthesis and immunomodulatory activities of Helicobacter pylori lipophilic terminus of lipopolysaccharide including lipid A

Helicobacter pylori, a Gram-negative bacterium, causes gastroduodenal inflammatory diseases such as chronic gastritis and peptic ulcers, and is also a risk factor for gastric carcinogenesis. In this article, we review recent developments and findings in the chemical synthesis and immunomodulatory activities of H. pylori lipid A and 3-deoxy-d-manno-2-octulosonic acid (Kdo)–lipid A, to clarify the structural basis for the inflammatory response to H. pylori LPS. The synthetic methods include a new divergent synthetic approach with a widely applicable key intermediate for other types of lipid A structures, as well as a selective α-glycosylation reaction between Kdo and lipid A. Cytokine induction assays of the chemically synthesized lipid A structures showed selective cytokine induction depending on the patterns of acyl groups and phosphate groups. The results of cytokine induction assay suggested that H. pylori LPS can modulate the immune response during infection, and also plays a role in chronic inflammatory responses.